The document discusses pharmacokinetic stereoselectivity. It covers absorption, distribution, metabolism, and elimination of enantiomers. For absorption, carrier transporters can cause stereoselective intestinal transport. Distribution is affected by stereoselective protein binding. Metabolism often shows substrate, product, or substrate-product stereoselectivity. Elimination can involve stereoselective renal clearance through protein binding or active secretion/reabsorption. Many examples are given to illustrate different types of stereoselectivity across the pharmacokinetic process.

1. Pharmacokinetics
stereoselectivity
PRESENTED BY: SWAFVAN K
M PHARM FIRST YEAR
PHARMACEUTICAL CHEMISTRY

2. Pharmacokinetics stereoselectivity
Absorption
•Passive intestinal absorption
•Carrier transporter stereoselectivity
Distribution
•Protein binding
•Tissue distribution
Metabolism
•First pass metabolism
•Phase 1 and Phase2 metabolism
Elimination

3. Absorption and stereoselectivity
• Passive intestinal absorption:
For majority of racemic drugs, absorption
appears to be by passive diffusion, provided no
stereoselectivity.
• Carrier mediated transporter:
Stereo selective intestinal transporter is the main
cause for marked difference in the oral
absorption of enantiomers.
L- Methotrexate have 40 fold higher Cmax and AUC
than D- Methotrexate

4. Absorption and stereoselectivity
 There was 15% difference in bioavailability of the
enantiomers of atenolol, Although it was postulated
that this was a result of an enantio selective active
absorption.
 Esomeprazole is more bioavailable than racemic
omeprazole.
 In case of L-dopa & methotrexate, enantioselectivity
would affect only the rate and not to the extent, of
absorption.
 Although L-dopa is absorbed much more rapidly than
D-dopa, they are both absorbed to the same extent.

5. DISTRIBUTION
Stereo selectivity in drug distribution may
occur as a result of binding to either plasma or
tissue proteins and transport via specific
tissue uptake and storage mechanisms
The majority of drugs bind in a reversible
manner to plasma proteins, notably to human
serum albumin(HSA) and/or α-acid
glycoprotein(AGP).

6. DISTRIBUTION
 The enantiomers may display different magnitudes of
stereoselectivity b/w the various proteins found in plasma.
Eg :- The R-propanolol binding to albumin is greater than S-
propanolol. The opposite is observed for α1 – acid
glycoprotein.
 S-warfarin is more extensively bound to albumin than R-
warfarin, hence it has lower volume of distribution.
 Levocetrizin has smaller volume distribution than its dextro
isomer
 d-propanolol more extensively bound to proteins than l-
propanolol

7. DISTRIBUTION
R-propanolol
• Highly albumin bound
• Less potent
• Highly metabolized
• Low plasma concentration
S-propanolol
• Highly bound to AAG available
as unbound.
• 40-100 time more potent.
• Less metabolized.
• Highly plasma concentration.

8. DISTRIBUTION
• There is enantio selective protein binding interaction
reported b/w warfarin & lorazepam acetate.
 R,S-warfarin allosterically increased the binding of S-
lorazepam acetate , but there was no effect on them
R-enantiomer.
 Similarly , S-lorazepam acetate increased the binding
of R,S-warfarin.

9. DISTRIBUTION
 Many antiarrythmic drugs are marketed as racemates
such as disopyramide, encainide, flecainide,
mexiletine, propafenone, tocainide etc
 Plasma protein binding is stereo selective for most of
the drugs, resulting in up to two fold differences b/w
the enantiomers in their unbound fraction in plasma &
volume of distribution.

10. DISTRIBUTION
 Enantio selective tissue uptake, whis is in part a
consequence of enantio selective plasma protein binding,
has been reported.
 For example, the transport of ibuprofen into both synovial
and blister fluids is preferential for the S-enantiomer owing
to the higher free fraction of this enantiomer in plasma.
 In addition , the affinity of stereoisomers for binding sites
in specific tissues may also differ and contribute to stereo
selective tissue binding
Eg :- S-leucovorin accumulates in tumor cell invitro to a
greater degree than the R enantiomer

11. METABOLISM
 stereoselectivity in metabolism is probably responsible
for the majority of the differences observed in
enantioselective drug disposition
 Stereoselectivity in metabolism may arise from
differences in the binding of enantiomeric substrates
to the enzyme active site and/or be associated with
catalysis owing to differential reactivity and orientation
of the target groups to the catalytic site
 As a result, pair of enantiomers is frequently
metabolized at different rates and/or via different
routes to yield alternative products.

12. METABOLISM
 The stereoselectivity of the reactions of drug metabolism
may be classified into three groups in terms of their
selectivity with respect to the substrate, the product, or
both.
 substrate selectivity - one enantiomer is metabolized more
rapidly than the other
 product stereoselectivity - in which one particular
stereoisomer of a metabolite is produced preferentially
 substrate– product stereoselectivity - where one
enantiomer is preferentially metabolized to yield a
particular diastereoisomeric product

13. METABOLISM
 An alternative classification involves the
stereochemical consequences of the transformation
reaction. Using this approach, metabolic pathways
may be divided into five groups.
 Prochiral to chiral transformations
 Chiral to chiral transformations
 Chiral to diastereoisomer transformations
 Chiral to achiral transformations
 Chiral inversion

14. METABOLISM
Prochiral to chiral transformations
• metabolism taking place either at a prochiral
center or on an enantiotopic group within the
molecule.
For example,
The prochiral sulphide cimetidine undergoes
sulphoxidation to yield the corresponding
sulphoxide, the enantiomeric composition

15. METABOLISM
Prochiral to chiral transformations
For example,
1- The prochiral sulphide cimetidine undergoes
sulphoxidation to yield the corresponding sulphoxide,
the enantiomeric composition

16. METABOLISM
Prochiral to chiral transformations
For example,
2- Phenytoin undergoes stereoselective para- hydroxylation to
yield (S)-4’-hydroxyphenytoin in greater than 90% enantiomeric
excess following drug administration to man

17. METABOLISM
 Chiral to chiral transformations :
the individual enantiomers of a drug undergo metabolism at
a site remote from the center of chirality with no
configurational consequences.
For example,
(S)-warfarin undergoes aromatic oxidation mediated by CYP
2C9 in the 7- and 6-positions to yield (S)-7-hydroxy- and (S)-6-
hydroxywarfarin in the ratio 3.5: 1.

18. METABOLISM
 Chiral to diastereoisomer transformations:
a second chiral center is introduced into the drug either by
reaction at a prochiral center or via conjugation with a
chiral conjugating agent.
Eg;-
aliphatic oxidation of pentobarbitone and the keto-
reduction of warfarin to yield the corresponding
diastereoisomeric alcohol derivatives or the stereoselective
glucuronidation of oxazepam.

19. METABOLISM
 Chiral to achiral transformations :
the substrate undergoes metabolism at the center of chirality,
resulting in a loss of asymmetry.
Examples
 aromatization of the dihydropyridine calcium channel blocking
agents, e.g., Nilvadipine, to yield the corresponding pyridine
derivative

20. METABOLISM
 Chiral to achiral transformations :
Examples
 the oxidation of the benzimidazole proton pump inhibitors, e.g.,
Omperazole, which undergoes CYP 3A4–mediated oxidation at the chiral
sulphoxide to yield the corresponding sulphone
the reaction shows tenfold selectivity for the S-enantiomer in
terms of intrinsic clearance.

21. METABOLISM
 Chiral inversion:
one stereoisomer is metabolically converted into its
enantiomer with no other alteration in structure
Agents undergoing this type of transformations
 2-aryl propionic acid (2-APAs)
 NSAIDS (eg;ibuprofen, fenoprofen, flurbiprofen, ketoprofen)
 2-aryloxypropionic acid herbicide (eg;haloxyfop)

22. METABOLISM
 Chiral inversion:
In the case of the 2-APAs, the reaction is essentially
stereospecific, the less active, or inactive, R-enantiomers
undergoing inversion to the active S-enantiomers
Mechanism

23. METABOLISM
Stiripentol
 following oral administration of one enantiomer, it
undergoes acid catalysed racemization & both enantimers
are formed
In case of (S)-enantiomer- only minor quantities of (R)-
enantiomer could be detected because of glucoronidation
of (R)-enanatiomer in liver

24. METABOLISM
Flosiquinan
Following administration of either enantiomer of
flosiquinan,alternative enantiomer could be detected in
plasma.
(R)-enantiomer – AUC approximately 8% for (S)-enantiomer
(S)-enantiomer – AUC approximately 25 for (R)-enantiomer

25. RENAL EXCRETION
 Stereo selectivity in renal clearance may arise as a result
of either selectivity in protein binding, influencing
glomerular filtration and passive reabsorption, or active
secretion or reabsorption.
 Enantio selectivity in renal clearance with enantiomeric
ratios between 1.0 and 3.0
 In the case of the diastereoisomers quinine and quinidine
–clearance is about 24.7 and99 mLmin-1 respectively.

26. RENAL EXCRETION
 For those agents that undergo active tubular secretion,
interactions between enantiomers may occur such that
their excretion differs following administration as single
enantiomers versus the racemat.
 EXAMPLE:-1
Administration of the quinolone antimicrobial agent (S)-
ofloxacin with increasing amounts of the R-enantiomer to
the cynomolgus monkey results in a reduction in both the
total and the renal clearance of the S-enantiomer.
MECHANISM:- By competitive inhibition of transport
mechanism(organic cation transport system)

27. RENAL EXCRETION
EXAMPLE:-2
Differences in the total and the renal clearance of the
enantiomers of the uricosuric diuretic 5-dimethyl sulphamoyl-
6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid (DBCA).
Administration of the racemic drug to the monkey results in a
25% reduction in the total and the renal clearance, and a 30%
reduction in the tubular secretion clearance, of the
S-enantiomer in comparison to the values obtained following
administration of the single enantiomer
 corresponding reductions in the same parameters for (R)-DBCA
did not achieve statistical significance.

28. RENAL EXCRETION
EXAMPLE:-3
Coadministration of the racemic drug with probenecid
resulted in significant reductions in the tubular secretion of
both enantiomers but was stereoselective for (S)-DBCA, the
decrease in clearance being 53% and 14% for the S- and R-
enantiomers, respectively.

29. RENAL EXCRETION
EXAMPLE:-4
In case of pindolol, tubular secretion of (S)-enantiomer being
30% greater than that of (R)-enantiomer.
Both the renal and the tubular secretion clearance of both
enantiomers is inhibited by cimetidine, presumably by inhibition
of the renal organic cation transport system.
The renal clearance of (S) - pindolol, the enantiomer with the
greater renal and the tubular secretion clearance, was reduced
to a smaller extent (26%) than that of the R-enantiomer (34%)
It indicate that the secretion of the drug is mediated by more
than one transporter, and that cimetidine has differential
inhibitory properties.

30. THANK YOU!